Retroviral vectors have been constructed that express human factor IX and a modified form of the human factor VIII gene. Four factor IX constructs were assembled using different MLV enhancer elements in attempts to optimize expression in specific tissues. Two cell transplant system are under evaluation for factor IX production, a semi-permeable membrane device, and an in situ bone marrow transduction protocol. New class of retroviral vector was developed for the expression of factor VIII in which the factor VIII is produced from a spliced mRNA. These vectors produced low level of biologically active factor VIII in vitro. Optimization of factor VIII gene expression is being investigated using site-directed mutagenesis.